Prostate cancer is the most common non-cutaneous cancer and the second leading cause of cancer-related deaths for males in the Western world (Siegel R, et al., 2012, 62(1):10-29). Prostate cancers are initially androgen-dependent, and while androgen deprivation therapy (ADT) can induce marked tumor regression, resistance to ADT inevitably emerges, leading to castration-resistant prostate cancer (CRPC). The current standard care for treating CRPC is systemic, docetaxel-based chemotherapy, increasing the overall survival of patients by about 2 months compared to mitoxantrone-based therapy (Petrylak D P, et al., N Engl J Med. 2004; 351(15):1513-1520; Tannock I F, et al., N Engl J Med. 2004; 351(15):1502-1512). Recently, sipuleucel-T, cabazitaxel, abiraterone, MDV3100 and Radium-223 have shown more prolonged overall survival benefit and are approved by the FDA for treatment of the disease (Bishr M and Saad F., Nat Rev Urol. 2013; 10(9):522-528). However, none of these drugs are curative; they incrementally improve overall survival. The establishment of more effective therapeutic targets and drugs, specifically those targeting the molecular drivers of metastatic CRPC, is of critical importance for improved disease management and patient survival (Lin D, et al., Curr Opin Urol. 2013; 23(3):214-219).
Apoptosis, a cell death-inducing process important in the regulation of cell numbers in normal tissues, can be triggered by a variety of death signals from both extracellular and intracellular origins, and involves activation of caspases (intracellular cysteine proteases) that mediate the execution of apoptosis (Hensley P, et al., Biol Chem. 2013; 394(7):831-843). Human cancers are characterized by resistance to apoptosis, intrinsic or acquired, considered to be a key factor underlying resistance to therapeutic intervention, and promising new strategies have been developed based on drug-induced apoptosis (Gleave M, et al., Cancer Chemother Pharmacol. 2005; 56 Suppl 1:47-57). The treatment resistance of CRPC is thought to be based on an increased resistance to apoptosis by the prostate cancer cells and may be addressed by targeting anti-apoptotic genes and their products (Zielinski R R, et al., Cancer J. 2013; 19(1):79-89).
The Inhibitors of Apoptosis (IAP) form a family of functionally and structurally related proteins that have a major role in cell death regulation. They act as endogenous apoptosis inhibitors by binding to caspases, thereby suppressing apoptosis initiation. The human IAP family consists of 8 members that are characterized by the presence of 1 to 3 baculovirus inhibitor of apoptosis repeat (BIR) motifs that are involved in the binding of IAPs to caspases. There is increasing evidence that IAPs also affect other cellular processes, such as ubiquitin-dependent signalling events that activate nuclear factor κB (NFκB) transcription factors, which in turn drive the expression of genes important in cellular processes such as cell survival (Gyrd-Hansen M and Meier P. Nat Rev Cancer. 2010; 10(8):561-574). Due to their ability to control cell death and elevated expression in a variety of cancer cell types, IAP proteins are attractive targets for the development of novel anti-cancer treatments (de Almagro M C and Vucic D. Exp Oncol. 2012; 34(3):200-211). Four IAP members, i.e. XIAP, survivin, cIAP1 and cIAP2, have been reported to be up-regulated in prostate cancer (Krajewska M, et al., Clin Cancer Res. 2003; 9(13):4914-4925). Survivin in particular is promising as a potential therapeutic target for the disease (Rodriguez L, et al., Biochem Pharmacol. 2013; 86(11):1541-1554 Carrasco R A, et al., Mol Cancer Ther. 2011; 10(2):221-232).
The BIRC6 gene (BRUCE/APOLLON) encodes a 528 kDa protein in mammals, consisting of a single N-terminal BIR domain and a C-terminal ubiquitin-conjugating (UBC) domain; the latter has chimeric E2/E3 ubiquitin ligase activity as well as anti-apoptotic activity (Bartke T, et al., Mol Cell. 2004; 14(6):801-811). Through its BIR domain, BIRC6 protein can bind to active caspases, including caspases-3, 6, 7 and 9 and such interactions have been shown to underlie its ability to inhibit the caspase cascade and ultimately apoptosis (Bartke T, et al., Mol Cell. 2004; 14(6):801-811). Through its UBC domain, BIRC6 facilitates proteasomal degradation of pro-apoptotic proteins, including caspase-9 (Hao Y, et al., Nat Cell Biol. 2004; 6(9):849-860), SMAC/DIABLO (Hao Y, et al., Nat Cell Biol. 2004; 6(9):849-860; Qiu X B and Goldberg A L. J Biol Chem. 2005; 280(1):174-182), and HTRA2/OMI (Bartke T, et al., Mol Cell. 2004; 14(6):801-811; Sekine K, et al., Biochem Biophys Res Commun. 2005; 330(1):279-285). Elevated expression of BIRC6 has been found in a variety of cancers, i.e. childhood de novo acute myeloid leukemia (Sung K W, et al., Clin Cancer Res. 2007; 13(17):5109-5114), colorectal cancer (Bianchini M, et al., Int J Oncol. 2006; 29(1):83-94), neuroblastoma (Bartke T, et al., Mol Cell. 2004; 14(6):801-811; Lamers F, et al., BMC Cancer. 2012; 12:285), melanoma (Tassi E, et al., Clin Cancer Res. 2012; 18(12):3316-3327) and non-small cell lung cancer (Dong X, et al., J Thorac Oncol. 2013; 8(2):161-170). Furthermore, BIRC6 has been implicated in maintaining resistance against cell death stimuli [Chen Z, et al., Biochem Biophys Res Commun. 1999; 264(3):847-854; Chu L, et al., Gene Ther. 2008; 15(7):484-494). In contrast to other IAPs, BIRC6 has been shown to have a cytoprotective role, essential for survival of mammalian cells (Hao Y, et al., Nat Cell Biol. 2004; 6(9):849-860; Qiu X B, et al., EMBO J. 2004; 23(4):800-810). BIRC6 is also known for its essential role in regulating cytokinesis, a final event of cell division (Pohl C and Jentsch S. Cell. 2008; 132(5):832-845). The dual roles of BIRC6 in cell death and division processes resemble those of survivin, and render it a promising target for therapy of a variety of cancers (Martin S J. Nat Cell Biol. 2004; 6(9):804-806).
Therapeutic options for castration resistant prostate cancer (CRPC) treatment have changed considerably with the recent FDA approvals of newer agents that improve patient survival. In particular, Enzalutamide (ENZ), a second generation androgen receptor antagonist approved for treating metastatic CRPC in post-docetaxel and more recently, pre-docetaxel setting. However, within 2 years of clinical practice, development of ENZ resistance was evident in majority of patients (Claessens et al. 2014) and no known therapies were shown to be effective to ENZ-resistant CRPC to-date. Thus, a novel therapeutic agent that can effectively suppress ENZ-resistant CRPC would be useful.